CA2277141A1 - Process for preparing conjugate vaccines including free protein and the conjugate vaccines, immunogens, and immunogenic reagents produced by this procedure - Google Patents

Process for preparing conjugate vaccines including free protein and the conjugate vaccines, immunogens, and immunogenic reagents produced by this procedure Download PDF

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Publication number
CA2277141A1
CA2277141A1 CA002277141A CA2277141A CA2277141A1 CA 2277141 A1 CA2277141 A1 CA 2277141A1 CA 002277141 A CA002277141 A CA 002277141A CA 2277141 A CA2277141 A CA 2277141A CA 2277141 A1 CA2277141 A1 CA 2277141A1
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Prior art keywords
protein
conjugate
polysaccharide
mixture
hapten
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CA002277141A
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French (fr)
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CA2277141C (en
Inventor
Andrew Lees
James J. Mond
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Henry M Jackson Foundation for Advancedment of Military Medicine Inc
Original Assignee
Andrew Lees
James J. Mond
The United States Of America As Represented By The Secretary Of The Army
Henry M. Jackson Foundation For The Advancement Of Military Medicine
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Application filed by Andrew Lees, James J. Mond, The United States Of America As Represented By The Secretary Of The Army, Henry M. Jackson Foundation For The Advancement Of Military Medicine filed Critical Andrew Lees
Publication of CA2277141A1 publication Critical patent/CA2277141A1/en
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Publication of CA2277141C publication Critical patent/CA2277141C/en
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Expired - Fee Related legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/385—Haptens or antigens, bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0006—Contraceptive vaccins; Vaccines against sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/81—Carrier - bound or immobilized peptides or proteins and the preparation thereof, e.g. biological cell or cell fragment as carrier

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Virology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)

Abstract

A process for preparing a protein-polysaccharide conjugate includes racting a protein with a polysaccharide to produce a mixture including a proteinpolysaccharide conjugate and free protein. At least one unreacted reagent or low molecular weight component is removed from this mixture, without removing all of the free protein, to provide a purified mixture that contains the protein-polysaccharide conjugate and free protein. This purified mixture can be used as a conjugate vaccine, immunogen, or immunological reagent. Keeping the free protein in the purified mixture with the conjugate saves time and money in the conjugate production process. In another aspect of the invention, the purified mixture of the protein-polysaccharide conjugate and free protein is reacted with a hapten to produce a conjugate mixture including a haptenprotein conjugate and a hapten-protein-polysaccharide conjugate. Alternatively, the hapten-protein conjugate can be prepared first, this conjugate then reacting with a polysaccharide reagent to produce the conjugate mixture. This conjugate mixture can be treated further to remove the free hapten. The conjugate mixture, including the hapten-protein-polysaccharide conjugate and the hapten-protein conjugate, also can be used as a conjugate vaccine, immunogen, or immunological reagent.

Claims (32)

  1. WE CLAIM:

    A process for preparing a protein-polysaccharide conjugate, comprising:
    reacting a protein with a polysaccharide to produce a mixture including a protein-polysaccharide conjugate and free protein; and removing at least one unreacted reagent or low molecular weight component from the mixture to provide a purified mixture that contains the protein-polysaccharide conjugate and free protein.
  2. 2. A process according to claim 1, wherein the reagent or low molecular weight component is removed by dialysis.
  3. 3. A process according to claim 1, wherein the reagent or low molecular weight component is removed by ultrafiltration.
  4. 4. A process according to claim 1, further including combining the purified mixture with a pharmaceutically acceptable medium or delivery vehicle.
  5. 5. A process according to claim 4, wherein the pharmaceutically acceptable medium or delivery vehicle is at least one member selected from the group consisting of water, petroleum oil, animal based oil, vegetable oil, peanut oil, soybean oil, mineral oil, sesame oil, saline, aqueous dextrose, and a glycerol solution.
  6. 6. A process according to claim 1 , wherein the purified mixture contains 5-90%
    free protein, by weight, based on the total protein content in the purified mixture.
  7. 7. A process according to claim 6, wherein the purified mixture contains 5-30%
    free protein, by weight, based on the total protein content in the purified mixture.
  8. A process according to claim 1, wherein, prior to reacting the protein and polysaccharide together, the polysaccharide is activated using an organic cyanylating reagent.
  9. 9. A process according to claim 8, wherein the organic cyanylating reagent is at least one member selected from the group consisting of l-cyano-4-(dimethylamino) pyridinium tetrafluoroborate, N-cyanotriethyl-ammonium tetrafluoroborate, and p-nitrophenylcyanate.
  10. 10. A process according to claim 8, wherein the organic cyanylating reagent is 1-cyano-4-(dimethylamino)-pyridinium tetrafluoroborate.
  11. 11. A process according to claim 1, wherein the protein is a microbial protein and the polysaccharide is a microbial polysaccharide.
  12. 12. A process according to claim 11, wherein the protein and polysaccharide are coupled together through a spacer.
  13. 13. A process according to claim 12, wherein the spacer is a thio-ether spacer.
  14. 14. A process according to claim 1, wherein the protein is at least one member selected from the group consisting of lipoprotein D, tetanus toxoid, diphtheria, and pertussis toxoid.
  15. 15. A process according to claim 1, wherein the polysaccharide is at least one member selected from the group consisting of a capsular polysaccharide from Haemophilus in~l uenza type b, dextran, Neisseria meningiditis polysaccharide type C, Vi antigen, and pneumococcal polysaccharide.
  16. 16. A process for preparing a hapten-protein-polysaccharide conjugate, comprising:
    reacting a protein with a polysaccharide to produce a mixture including a protein-polysaccharide conjugate and free protein;
    removing at least one unreacted reagent or low molecular weight component from the mixture to provide a purified mixture that contains the protein-polysaccharide conjugate and free protein; and reacting a hapten with the purified mixture to thereby provide a conj ugate mixture including a hapten-protein conjugate and a hapten-protein-polysaccharide conjugate.
  17. 17. A process according to claim 16, further including removing excess hapten from the conjugate mixture to thereby provide a purified conjugate mixture.
  18. 18. A process according to claim 17, wherein the hapten is removed from the conjugate mixture by dialysis to provide the purified conjugate mixture.
  19. 19. A method according to claim 18, further including combining the purified conjugate mixture with a pharmaceutically acceptable medium or delivery vehicle.
  20. 20. A method according to claim 19, wherein the pharmaceutically acceptable medium or delivery vehicle is at least one member selected from the group consisting of water, petroleum oil, animal based oil, vegetable oil, peanut oil, soybean oil, mineral oil, sesame oil, saline, aqueous dextrose, and a glycerol solution.
  21. 21. A process according to claim 16, wherein the hapten is a peptide selected from the group consisting of luteinizing hormone releasing hormone, peptides derived from E coli, and malaria derived peptides.
  22. 22. A process for preparing a hapten-protein-polysaccharide conjugate, comprising:
    reacting a protein with a hapten to produce a hapten-protein conjugate; and reacting the hapten-protein conjugate with a polysaccharide to thereby provide a conjugate mixture including the hapten-protein conjugate and a hapten-protein-polysaccharide conjugate.
  23. 23. A method according to claim 22, further including combining the conjugate mixture with a pharmaceutically acceptable medium or delivery vehicle.
  24. 24. A method according to claim 23, wherein the pharmaceutically acceptable medium or delivery vehicle is at least one member selected from the group consisting of water, petroleum oil, animal based oil, vegetable oil, peanut oil, soybean oil, mineral oil, sesame oil, saline, aqueous dextrose, and a glycerol solution.
  25. 25. A process according to claim 22, wherein the hapten is a peptide selected from the group consisting of luteinizing hormone releasing hormone, peptides derived from E coli, and malaria derived peptides.
  26. 26. A material comprising:
    a protein-polysaccharide conjugate and free protein, wherein after conjugation to produce the protein-polysaccharide conjugate, the free protein is not separated from the protein-polysaccharide conjugate, wherein said material has an immunogenicity substantially the same as or greater than that of the corresponding protein-polysaccharide conjugate that has free protein removed.
  27. 27. A material according to claim 26, wherein the material is a vaccine.
  28. 28. A material according to claim 26, wherein the material is an immunogen.
  29. 29. A material according to claim 26, wherein the material is an immunological reagent.
  30. 30. A material produced by the process of claim 1.
  31. 31. A material produced by the process of claim 16.
  32. 32. A material produced by the process of claim 22.
CA2277141A 1997-01-08 1998-01-07 Process for preparing conjugate vaccines including free protein and the conjugate vaccines, immunogens, and immunogenic reagents produced by this procedure Expired - Fee Related CA2277141C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US3465397P 1997-01-08 1997-01-08
US60/034,653 1997-01-08
PCT/US1998/000111 WO1998030239A2 (en) 1997-01-08 1998-01-07 Process for preparing conjugate vaccines including free protein and the conjugate vaccines, immunogens, and immunogenic reagents produced by this procedure

Publications (2)

Publication Number Publication Date
CA2277141A1 true CA2277141A1 (en) 1998-07-16
CA2277141C CA2277141C (en) 2012-04-24

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CA2277141A Expired - Fee Related CA2277141C (en) 1997-01-08 1998-01-07 Process for preparing conjugate vaccines including free protein and the conjugate vaccines, immunogens, and immunogenic reagents produced by this procedure

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US (3) US6248334B1 (en)
EP (1) EP1015027B1 (en)
JP (1) JP2001508774A (en)
AT (1) ATE399023T1 (en)
AU (1) AU736409B2 (en)
CA (1) CA2277141C (en)
DE (1) DE69839642D1 (en)
WO (1) WO1998030239A2 (en)

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Also Published As

Publication number Publication date
EP1015027B1 (en) 2008-06-25
WO1998030239A3 (en) 1999-02-11
DE69839642D1 (en) 2008-08-07
AU736409B2 (en) 2001-07-26
US6248334B1 (en) 2001-06-19
CA2277141C (en) 2012-04-24
US20050074460A1 (en) 2005-04-07
WO1998030239A2 (en) 1998-07-16
EP1015027A2 (en) 2000-07-05
ATE399023T1 (en) 2008-07-15
AU5731798A (en) 1998-08-03
US20020054879A1 (en) 2002-05-09
US7166708B2 (en) 2007-01-23
US6756041B2 (en) 2004-06-29
JP2001508774A (en) 2001-07-03

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